Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability

ABSTRACT

A fibrate oral formulation with improved bioavailability when compared to commercially available formulations containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C 8-12  fatty acid ester of polyethylene glycol, fatty acids, or combinations thereof useful for the treatment of hypercholesterolaemia or hypertriglyceridaemia in mammals.

FIELD OF THE INVENTION

[0001] The present invention relates to a non-aqueous pharmaceuticalformulation of fenofibrate or fenofibrate derivatives having an improvedoral bioavailability when compared to a commercial availableformulation.

BACKGROUND OF THE INVENTION

[0002] Fenofibrate is a fibrate used in the treatment of endogenoushyperlipidaemias, hypercholesterolaemias and hypertriglyceridaemias inadults. The preparation of fenofibrate is disclosed in U.S. Pat. No.4,058,552. Fenofibric acid, the active metabolite of fenofibrate,produces reductions in total cholesterol, LDL cholesterol,apolipoprotein B, total triglycerides and triglyceride rich lipoprotein(VLDL) in treated patients. Also, treatment with fenofibrate results inincreases in high-density lipoprotein (HDL) and apoproteins apoAI andapoAII. Prolonged treatment with fenofibrate at the rate of 300 to 400mg per day makes it possible to obtain a reduction in total cholesterolof 20 to 25% and a reduction in the levels of triglycerides of 40 to50%. It thus opposes the development of arteriosclerosis. The customaryadult fenofibrate dosage is three gelatin capsules per day, eachcontaining 100 mg of fenofibrate.

[0003] Fenofibrate is not soluble in water, which limits its absorptionin the gastrointestinal (GI) tract. To remedy this problem, researchgroups have tried a multitude of strategies. In U.S. Pat. Nos. 4,800,079and 4,895,726 micronized fenofibrate formulations of are disclosed. InU.S. Pat. No. 6,277,405 the immediate release of micronized fenofibratein a tablet or in the form of granules inside a capsule is shown. InU.S. Pat. No. 6,074,670 the immediate release of micronized fenofibratein a solid state is shown. In U.S. Pat. No. 5,880,148 the combination offenofibrate and vitamin E is discussed, this formulation is claimed tobe useful as an antiatheromatous drug and exhibit a synergistic effectin regards to protecting low-density lipoproteins (LDL) from oxidation.In U.S. Pat. No. 5,827,536 the use of diethylene glycol monoethyl ether(DGME) as solubilizer is discussed and an enhancement in bioavailabilityclaimed. In U.S. Pat. No. 5,545,628 the combination of fenofibrate withone or more polyglycolyzed glycerides is disclosed.

[0004] In order to prepare the solid formulations of Fenofibrate, thecompound is normally dissolved in a proper solvent or solubilizers.Fenofibrate is known to be soluble in many different solubilizers,including anionic (e.g. SDS) and non-ionic (e.g. Triton X-100)surfactants, complexing agents (N-methyl pyrrolidone) (Temeljotov et al(1995) Farmacevtski Vestnik (Slovenia), 46/(Special Issue)).

[0005] The technology developed to increase the bioavailability offenofibrate includes elements and process steps that increase the costof production making them commercially unattractive. If a formulationfor the use fenofibrate and its method of preparation of saidformulation could be simplified while increasing the bioavailability offenofibrate, the resulting product would satisfy an existing need inthis field. The present invention provides such a product, a liquid orsemi-solid formulation with improved bioavailability for oraladministration of fenofibrate or fenofibrate derivatives wherein theparticle size of the active agent is not critical to the bioavailabilityof the product.

SUMMARY OF THE INVENTION

[0006] The object of the present invention includes an oralpharmaceutical formulation with improved bioavailability when comparedto a commercial available formulation comprising a therapeuticallyeffective amount of the a fibrate dissolved in N-alkyl derivative of2-pyrrolidone, ethylene glycol monoether, C₈₋₁₂ fatty acid ester ofpolyethylene glycol or combinations thereof. The present inventionadditionally includes oral pharmaceutical formulations with improvedbioavailability comprising a therapeutically effective amount offenofibrate or a fenofibrate derivative in a N-alkyl derivative of2-pyrrolidone, ethylene glycol monoether, C₈₋₁₂ fatty acid ester ofpolyethylene glycol or combinations thereof wherein the bioavailabilityof the active ingredient is enhanced due to a significant (P<0.05)change in the rate, C_(max), and/or extent, AUC_(0-∞), of absorptionwhen compared to a commercial available formulation such as Lipanthyl®(trade mark of Groupe Fournier) or TriCor® (trade mark of AbbottLaboratories).

[0007] In an alternate embodiment of the invention a fibratepharmaceutical formulation containing a therapeutically effective amountof the fenofibrate or its derivatives dissolved in N-alkyl derivative of2-pyrrolidone, ethylene glycol monoether, C₈₋₁₂ fatty acid ester ofpolyethylene glycol or combinations thereof and at least one surfactantis disclosed.

[0008] According to a further aspect of the invention, there is provideda method for treating a mammal with hypercholesterolaemia orhypertriglyceridaemia comprising the oral administration of a fibrateformulation containing a therapeutically effective dose of fenofibrateor a fenofibrate derivative dissolved in N-alkyl derivative of2-pyrrolidone, ethylene glycol monoether, fatty acids, fatty acids,C₈₋₁₂ fatty acid ester of polyethylene glycol or combinations thereof.

[0009] The present invention includes an self-emulsifying oralpharmaceutical formulation with improved bioavailability comprising atherapeutically effective amount of fenofibrate or a fenofibratederivative, at least one non-ionic hydrophobic surfactant (HLB valuelower than or equal to 10), and a water miscible fenofibrate solubilizerselected from N-C₁₋₄ alkyl derivative of 2-pyrrolidone, ethylene glycolmonoether, or combinations thereof mixed with at least one of fattyacids or C₈₋₁₂ fatty acid ester of polyethylene glycol.

[0010] The present invention also includes oral self-emulsifyingpharmaceutical formulations with improved bioavailability when comparedto a commercial available formulation comprising a therapeuticallyeffective amount of fenofibrate or a fenofibrate derivative, one or morenon-ionic surfactant with an HLB value higher about 10, one or morenon-ionic co-surfactant with a HLB value lower or equal to about 6,provide that the surfactant/co-surfactant combination has a HLB valuelower than or equal to about 10 and a water miscible fenofibratesolubilizer selected from N-C₁₋₄ alkyl derivative of 2-pyrrolidone,ethylene glycol monoether, or combinations thereof mixed with at leastone of fatty acids or C₈₋₁₂ fatty acid ester of polyethylene glycol.

[0011] The present invention additionally includes an oralself-emulsifying pharmaceutical formulation with improvedbioavailability comprising a therapeutically effective amount of thefenofibrate or a fenofibrate derivative, one or more non-ionicsurfactant with an HLB value between 10 and 18, one or more non-ionicco-surfactant with a HLB value between 2 and 6, and a fenofibratesolubilizer selected from water miscible N-C₁₋₄ alkyl derivative of2-pyrrolidone, water miscible ethylene glycol monoether, fatty acids,C₈₋₁₂ fatty acid ester of polyethylene glycol and combinations thereofwherein the bioavailability of the active ingredient is significantlyenhanced when compared to a commercial available formulation due to asignificantly (P<0.05) enhanced rate (C_(max), reduction in the time toreach maximum plasma levels, T_(max)) and/or extent of absorption(AUC_(0-∞)) of the fibrate.

[0012] In an embodiment of the present invention fibrate formulationsdescribed above wherein the improvement in C_(max) is at least 1.2 timesthan that for commercial formulation and/or the AUC_(0-∞)improvement isat least 1.5 times that of commercial formulation are disclosed.

[0013] The scope of the invention includes a pharmaceutical dosage unitfor oral administration comprising of a fibrate formulation containing atherapeutically effective dose of fenofibrate or a fenofibratederivative dissolved in N-alkyl derivative of 2-pyrrolidone, ethyleneglycol monoether, fatty acids, C₈₋₁₂ fatty acid ester of polyethyleneglycol or combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention provides non-aqueous formulations withenhanced systemic absorption of fenofibrate and/or derivatives offenofibrate when compared to a commercial available formulation.

[0015] Due to the physicochemical properties of fibrates such asfenofibrate, the systemic absorption of the drug is believed to bedissolution rate limited. By providing an oral formulation wherein thefenofibrate or fenofibrate derivative is dissolved in a water miscibleorganic solvent such as the N-alkyl derivatives of 2-pyrrolidone,ethylene glycol monoether, C₈₋₁₂ fatty acid ester of polyethylene glycolor combinations thereof. The water miscible solvent or solubilizer usedin the present invention additionally may act as an agent that preventsor minimizes the crystallization of fibrate in the formulation uponcontact with an aqueous environment. The fibrate solubilizer may be acomplexing agent soluble in water. With the complete dissolution of thefibrate, the fibrate solution allows for an increase in absorption bythe patient. The ease with which the fenofibrate or fenofibratederivative dissolves in a solvent is inversely proportional to theparticle size of the fibrate. Therefore, the present invention includesan oral fibrate formulation comprising fenofibrate or a fenofibratederivative and a water miscible organic solubilizer that allows thecomplete dissolution of the fenofibrate or a fenofibrate derivative andprevents or minimizes the crystallization of fibrate in the formulationupon contact with an aqueous environment. The present invention includesfibrate formulation wherein the fibrate to fibrate solubilizer weightratio is between about 1:1 and about 1:100.

[0016] As used in this application, the term “fatty acid” represents aC₁₋₃₀ unbranched or branched, saturated or unsaturated hydrocarbon chainand a terminal carboxyl group.

[0017] The solubilizer comprises the combination of solvents,surfactants, optional co-surfactants, and stabilizing agents used in theformulation. In an embodiment of the present invention the fibratesolubilizer may contain an oily component and a non-oily component. Theoily component of the solubilizer may consist of alcohols, propyleneglycol, polyethylene glycol, propylene glycol esters, medium chainmono-, di-, or triglycerides, long chain fatty acids, naturallyoccurring oils, and a mixture thereof. The oily component of thesolubilizer may contain non-surface active oils, which have nohydrophile lipophile balance value. The non-oily component of thesolubilizer may contain molecules with highly polar functionalities suchas carbonyl groups as well as primary amines with short chain (C₁-C₃)alkyl groups. The present invention includes self-emulsifying fibrateformulation wherein the fibrate to fibrate solubilizer weight ratio isbetween about 1:1 and about 1:100.

[0018] In a further embodiment of the present invention an oralfenofibrate formulation comprising fenofibrate or a fenofibratederivative and a water miscible fibrate solubilizer is N-alkylderivative of 2-pyrrolidone, ethylene glycol monoether, C₈₋₁₂fatty acidester of polyethylene glycol or combinations thereof is provided. Theformulations described may further contain a gelling agent that altersthe texture of the final formulation through formation of a gel.

[0019] Gelling agents used in the present invention include but are notlimited to carrageenan, cellulose gel, colloidal silicon dioxide,gelatin, propylene carbonate, carbonic acid, alginic acid, agar,carboxyvinyl polymers or carbomers and polyacrylamides, acacia, estergum, guar gum, gum arabic, ghatti, gum karaya, tragacanth, terra,pectin, tamarind seed, larch arabinogalactan, alginates, locust bean,xanthan gum, starch, veegum, tragacanth, polyvinyl alcohol, gellan gum,hydrocolloid blends, and povidone.

[0020] The present invention further includes an oral self-emulsifyingfibrate formulation with improved oral bioavailability comprising atherapeutically effective amount of the fenofibrate or fenofibratederivative dissolved in a water miscible fibrate solubilizer selectedfrom N-C₁₋₄ alkyl derivative of 2-pyrrolidone or ethylene glycolmonoether and mixtures thereof, in combination with at least one offatty acids and/or C₈₋₁₂ fatty acid ester of polyethylene glycol and atleast one non-ionic surfactant with a high HLB value lower than or equalto 10.

[0021] The present invention also provides an oral self-emulsifyingformulation wherein the fenofibrate is dissolved in one or morenon-ionic surfactant with an HLB value higher or equal to about 10, oneor more non-ionic co-surfactant with a HLB value lower or equal to about6, and a water miscible fenofibrate solubilizer selected from N-C₁₋₄alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C₈₋₁₂fatty acid ester of polyethylene glycol and combinations thereof,wherein the resulting fenofibrate self-emulsifying formulation allowsfor an improved systemic absorption of the fenofibrate by the patient.

[0022] The term “HLB” value is defined as hydrophilic-lipophilic balanceand defines the relative hydrophilicity and hydrophobicity of thesurfactant. Surfactants with lower HLB values are more hydrophobic, andhave greater solubility in oils, while surfactants with higher HLBvalues are more hydrophilic, and have greater solubility in aqueoussolutions. Surfactants having an HLB value less than about 10 areconsidered to be hydrophobic surfactants. Therefore hydrophilicsurfactants have HLB values greater than about 10. Combinations ofhydrophilic surfactants and hydrophobic surfactants thereof are withinthe scope of the present invention.

[0023] The surfactants used in the present invention include thosehaving a HLB value of less than or equal to 10. These surfactants mayinclude propylene glycols, glyceryl fatty acids, glyceryl fatty acidesters, polyethylene glycol esters, propylene glycol laureate, glycerylglycol esters, polyglycolyzed glycerides, propylene glycol esters orpartial esters and polyoxyethyl steryl ethers. Mixtures of surfactantsare also included in the scope of the invention. These surfactants,mixtures, and other equivalent compositions having an HLB less than orequal to 10 may be used for the self-emulsifying formulation.

[0024] The use of surfactants with an HLB greater than 10 are within thescope of the present invention. Surfactants that have a HLB valuegreater than 10 may be used in combination with other surfactant asco-surfactants. Suitable co-surfactants include glyceryl glycol esters,polyethylene glycol esters, polyglycolyzed glycerides, polyoxyethyleneglycerol esters, oleate or laureate ester of a polyalcohol copolymerizedwith ethylene oxide and a mixture thereof. Examples of commerciallyavailable surfactants are Labrasol, Gelucire 44/14 and Tween 80

[0025] The term “fenofibrate” is a fibrate and is defined as a compoundof formula (I), 2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic acid1-methylethyl ester:

[0026] The term “fenofibrate derivatives” is defined as a compound offormula (II)

[0027] wherein

[0028] R₁ represents a phenyl group or a phenyl group substituted by oneor more CH₃, CF₃ or by halogens;

[0029] R₂ and R₃ independently represent a hydrogen atom or a halogenatom (preferably fluorine, chlorine, or bromine), an C₁₋₄ alkyl or anC₁₋₅ alkoxy or one of the following groups: CF₃, SCH₃, SOCH₃, SO₂CH₃, orOH; and

[0030] Y represents one of the following groups: OH; C₁₋₅ alkoxy,preferably in C₁-C₄; —NR₄R₅ ; —NHCH₂CH₂NR₄R₅; or —O—C₁₋₆ alkylene-NR₄R₅,with the alkylene having, in particular, two to six atoms of carbon, andwith R₄ and R₅ being identical or different and each representing ahydrogen atom or one of the following groups: C₁₋₅ alkyl, C₃-C₇cycloalkyl, preferably C₅₋₆ cycloalkyl; C₆₋₁₀ aryl or aryl substitutedon the aromatic residue by one or more halogen, methyl, or —CF₃ groups;or else R₄ and R₅ constitute, together with the nitrogen atom to whichthey are connected, one of the following groups: either ann-heterocyclic group having 5 to 7 vertices capable of enclosing asecond heteroatom selected from N, O, and S, and capable of beingsubstituted; or else an amide residue derived from lysine or cysteine;including the pharmaceutically acceptable salts, esters, amides andprodrugs thereof

[0031] wherein said derivative has a solubility not less than 0.5 mg/mlin the water miscible solubilizer used in the fibrate formulation objectof the present invention.

[0032] The scope of the present invention includes formulationssummarized in Tables 1A and 1B: TABLE 1A Quantitative representation offenofibrate formulations in the form of non-emulsifiable systems, suchas binary solutions Amount Ingredient (% w/w) Fenofibrate 5-50Solubilizer 5-50 Other possible formulation additives* 0-70

[0033] TABLE 1B Quantitative representation of self-emulsifyingformulations providing for enhanced systemic absorption of fenofibrateAmount Ingredient (% w/w) Fenofibrate  5-30 Total oleaginous component35-45 Solubilizer  5-30 Surfactant 10-15 Other possible formulationadditives*  5-15

[0034] The present invention includes a fenofibrate formulation whereinthe water miscible fenofibrate solubilizer includes the use of N-alkylderivatives 2-pyrrolidones, wherein the alkyl group has 1 to 4 carbons,C₆₋₈ethylene glycol monoethers, C₈₋₁₂ fatty acid ester of polyethyleneglycol, fatty acids or combinations thereof is provided. The presentinvention includes N-alkyl derivatives 2-pyrrolidone wherein the alkylgroup has 1 to 3 carbons.

[0035] The amount of fibrates such as fenofibrate, fenofibratederivatives or mixtures thereof contained in the formulation of thisinvention is not specifically restricted but may be any amountconvenient for pharmaceutical purposes. For filling a gel capsule, aconcentrated solution of up to the saturation point of the fibratesolubilizer may be of interest. For example the solubility offenofibrate in N-methyl-2-pyrrolidone is about 591 mg/ml, so aconcentrated fenofibrate solutions of >500 mg/ml would be of interestfor use in the oral formulation object of the present invention. Thepresent invention would also include fenofibrate inN-methyl-2-pyrrolidone solutions with concentrations below about 500mg/ml.

[0036] In an alternate embodiment of the present invention, thefenofibrate or fenofibrate derivative solubilizer is selected fromN-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone,N-isopropyl-2-pyrrolidone, N-butyl-2-pyrrolidone,N-(2-hydroxyethyl)-2-pyrrolidone, diethylene glycol monoethyl ether,polyethylene glycol mono- and diester of C₈₋₁₂ fatty acids andcombinations thereof. The invention includes the combination of theN-alkyl derivatives of 2-pyrrolidone with ethylene glycol monoetherand/or C₈₋₁₂ fatty acid ester of polyethylene glycol; or combinations offatty acids and C₈₋₁₂ fatty acid ester of polyethylene glycol. Theformulation object of the present invention may useN-methyl-2-pyrrolidone, diethylene glycol monoethyl ether, polyethyleneglycol mono- and diester of caproic acid, caprylic acid, capric acid,lauric acid or mixtures of polyethylene glycol mono- and diester ofcaproic acid, caprylic acid, capric acid, lauric acid with one or morefatty acids selected from caproic acid, caprylic acid, capric acid,lauric acid and mixtures thereof; and combinations thereof assolubilizers of fenofibrate. The mono- and diester of C₈₋₁₂ fatty acidsand combinations thereof also include use of Captex® 100 , Captex® 200,Captex® 200 E-6, Capmul® MCM, Capmul® PG-8, Capmul® PG-10, (AbitecCorp.) and Gelucire® 44/14, Gelucire® 50/13 (Gattefosse Corp.).Combinations of N-Methyl-2-Pyrrolidone and diethylene glycol monoethylether as fibrate solubilizers are within the scope of the presentinvention. The invention includes combinations of N-methyl-2-pyrrolidoneand diethylene glycol monoethyl ether wherein the weight rations ofN-methyl-2-pyrrolidone to diethylene glycol monoethyl ether is betweenabout 1:0.01 and about 0.01:1. The invention also includes combinationsof N-methyl-2-pyrrolidone and diethylene glycol monoethyl ether whereinthe weight rations of N-methyl-2-pyrrolidone to diethylene glycolmonoethyl ether is between about 1:0.1 and about 0.1:1.

[0037] In a further embodiment of the present invention, the watermiscible fibrate solubilizer is chosen from combinations of N-C₁₋₄ alkylderivative of 2-pyrrolidone or a ethylene glycol monoether orcombinations thereof, with one or more polyethylene glycol mono- ordiester of C₈₋₁₂ fatty acids or mixtures polyethylene glycol mono- anddiester of C₈₋₁₂ fatty acids and fatty acids. The weight ratio of theN-C₁₋₄ alkyl derivative of 2-pyrrolidone or a ethylene glycol monoetheror combinations thereof to one or more polyethylene glycol mono- anddiester of C₈₋₁₂ fatty acids or mixtures polyethylene glycol mono- anddiester of C₈₋₁₂ fatty acids and fatty acids is between about 100:1 toabout 1:4. The present invention includes rations between 20:1 to about1:4.

[0038] The amount of fibrate solubilizer used will depend on the dose offibrate; enough solubilizer should be used to maintain the fibrate insolution. The weight ratio fibrate to the fibrate solubilizer is chosenso as to obtain a complete dissolution of fenofibrate or fenofibratederivative. The fibrate: fibrate solubilizer ratio is chosen to obtain asolution whose fibrate concentration is below the saturation point. Theweight ratio of fibrate to fibrate solubilizer may be between about 1:1to about 1:100. The weight ratios include about 1:1 to about 1:10. Thefibrate:fibrate solubilizer weight ratio may also be between about 3:4to about 1:100. The fibrate:fibrate solubilizer weight ratio betweenabout 3:4 to about 1:10 is within the scope of the invention.

[0039] The present invention includes an oral fibrate formulationcomprising fenofibrate or a fenofibrate derivative and a water miscibleorganic solubilizer that allows the complete dissolution of thefenofibrate or a fenofibrate derivative and prevents or minimizes thecrystallization of fibrate in the formulation upon contact with anaqueous environment with an improved bioavailability equal to or greaterthat about 10%. The invention includes fibrate formulation comprising atherapeutically effective amount of the fenofibrate, a fenofibratederivative or combinations thereof and a N-alkyl derivative of2-pyrrolidone, or combinations of N-alkyl derivative of 2-pyrrolidones,ethylene glycol monoether, C₈₋₁₂ fatty acid ester of polyethylene glycolor combinations thereof. The bioavailability is enhanced due to asignificantly (P<0.05) enhanced rate (C_(max), reduction in the time toreach maximum plasma levels, T_(max)) and/or extent of absorption(AUC_(0-∞)). The % bioavailability enhancement value is defined as theratio obtained by formula (III):

{(AUC_(0-24 (fibrate formulation))/Dose_(fibrate formulation))/(AUC_(0-24 (Commercial formulation))/Dose_(Commercial formulation))}×100  (III)

[0040] The present invention includes the use of N-methyl-2-pyrrolidone(NMP) in a formulation to solubilize fenofibrate and/or its derivativeswith similar solubility profile, and enhance bioavailability after oraladministration to a % enhancement value equal to or greater than 50%.N-methyl-2-pyrrolidone is an organic liquid excipient and is also knownas 1-methyl pyrrolidinone, N-methyl-2-pyrrolidinone,1-methyl-5-pyrrolidinone, methylpyrrolidinone, N-methylpyrrolidinone,methylpyrrolidinone, N-methylpyrrolidone, M-pyrol, and NMP.

[0041] The present invention additionally includes an oralpharmaceutical formulation with improved oral bioavailability comprisinga therapeutically effective amount of fenofibrate, a fenofibratederivative or mixtures thereof and one or more solubilizers selectedfrom N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether,C₈₋₁₂ fatty acid ester of polyethylene glycol, mixtures of C₈₋₁₂ fattyacid ester of polyethylene glycol and fatty acids, or combinationsthereof wherein the bioavailability of said formulation is significantly(P<0.05) enhanced in both the rate (C_(max)) and the extent (AUC_(0-∞))of absorption as compared to that of a commercial formulation. Thepresent invention includes said formulations wherein the improvement inC_(max) is at least about 1.2 times that of a commercial formulationsuch as Lipanthyl® (trade mark of Groupe Fournier) or TriCor® (trademark of Abbott Laboratories) and/or the AUC_(0-∞) improvement is atleast about 1.5 times that of a commercial formulation such asLipanthyl® (trade mark of Groupe Fournier) or TriCor® (trade mark ofAbbott Laboratories).

[0042] The present invention further includes oral self-emulsifyingfibrate formulation with improved oral bioavailability comprising atherapeutically effective amount of the fenofibrate or fenofibratederivative dissolved in a water miscible fibrate solubilizer selectedfrom N-C₁₋₄ alkyl derivative of 2-pyrrolidone or ethylene glycolmonoether and mixtures thereof, in combination with at least one C₈₋₁₂fatty acid ester of polyethylene glycol and at least one non-ionicsurfactant with a high HLB value lower than or equal to 10 wherein theoral bioavailability of said formulation is significantly (P<0.05)enhanced in both the rate (C_(max)) and the extent (AUC_(0-∞)) ofabsorption as compared to that of a commercial formulation such asLipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark ofAbbott Laboratories). The present invention includes said formulationswherein the improvement in C_(max) is at least 1.2 times that acommercial formulation such as Lipanthyl® (trade mark of GroupeFournier) or TriCor® (trade mark of Abbott Laboratories) and/or theAUC_(-∞) improvement is at least 1.5 times that of a commercialformulation such as Lipanthyl® (trade mark of Groupe Fournier) orTriCor® (trade mark of Abbott Laboratories).

[0043] The present invention also provides an oral self-emulsifyingformulation wherein the fenofibrate is dissolved in one or morenon-ionic surfactant with an HLB value higher or equal to about 10, oneor more non-ionic co-surfactant with a HLB value lower or equal to about6, and a water miscible fenofibrate solubilizer selected from N-C₁₋₄alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C₈₋₁₂fatty acid ester of polyethylene glycol or mixtures of C₈₋₁₂ fatty acidester of polyethylene glycol and fatty acids, and combinations thereof,wherein the resulting fenofibrate self-emulsifying formulation allowsfor an improved systemic absorption of the fenofibrate by the patientand the oral bioavailability of said formulation is significantly(P<0.05) enhanced in both the rate (C_(max)) and the extent (AUC_(0-∞))of absorption as compared to that of a commercial formulation such asLipanthyl® (trade mark of Groupe Fournier) or TriCor® (trade mark ofAbbott Laboratories). The present invention includes said formulationswherein the improvement in C_(max) is at least 1.2 times that acommercial formulation such as Lipanthyl® (trade mark of GroupeFournier) or TriCor® (trade mark of Abbott Laboratories). and/or theAUC_(0-∞) improvement is at least 1.5 times that of a commercialformulation such as Lipanthyl® (trade mark of Groupe Fournier) orTriCor® (trade mark of Abbott Laboratories).

[0044] The present invention additionally includes an oralself-emulsifying pharmaceutical formulation with improvedbioavailability comprising a therapeutically effective amount of thefenofibrate or a fenofibrate derivative, one or more non-ionicsurfactant with an HLB value between 10 and 18, one or more non-ionicco-surfactant with a HLB value between 2 and 6, and a fenofibratesolubilizer selected from water miscible N-C₁₋₄ alkyl derivative of2-pyrrolidone, water miscible ethylene glycol monoether, C₈₋₁₂ fattyacid ester of polyethylene glycol or mixtures of C₈₋₁₂ fatty acid esterof polyethylene glycol and fatty acids, and combinations thereof whereinthe bioavailability of the active ingredient is significantly enhanced,wherein the fenofibrate may or may not be micronized. Thebioavailability when compared to a commercial available formulation isenhanced due to a significantly (P<0.05) enhanced rate (reduction in thetime to reach maximum plasma levels, T_(max)) and/or extent ofabsorption (AUC_(0-∞)).

[0045] The oral formulation object of the present invention may beprovided in the form of a solution, a self-emulsifying system, astraight binary system, semi-solid system or any other pharmaceuticallyacceptable form. The oral formulation may be encapsulated in a hard orsoft gelatin capsule, a starch capsule or any other pharmaceuticallyacceptable capsule.

[0046] The present invention includes a pharmaceutical formulation withimproved oral bioavailability when compared to a commercially availableformulation comprising a therapeutically effective amount of thefenofibrate, a fenofibrate derivative or mixtures thereof dissolved in asolubilizer selected from N-alkyl derivative of 2-pyrrolidone, ethyleneglycol monoether, C₈₋₁₂ fatty acid ester of polyethylene glycol ormixtures of C₈₋₁₂ fatty acid ester of polyethylene glycol and fattyacids, or mixtures thereof and at least one non-ionic surfactant with anHLB value higher or equal to about 10.

[0047] The present invention includes the use of surfactants selectedfrom sucrose esters, polysorbates, polyethylene glycosylated glycerides,PEGylated glycerides and combinations thereof. These non-ionicsurfactant may include mixtures of monoglycerides, diglycerides, andtriglycerides and monoesters and diesters of polyethylene glycol,polyethylene glycosylated almond glycerides, polyethylene glycosylatedcorn glycerides, polyethylene glycosylated caprylic/capric triglyceride,polysorbate 20, polysorbate 60, polysorbate 80, Polyoxyl 20 CetostearylEther, Polyoxyl 10 Oleyl Ether and combinations thereof. Additionallysuitable non-ionic surfactants include PEG stearate, PEG hydrogenatedcastor oil, PEG laurate, PEG apricot kernel oil esters, PEG caprylate,PEG caprate, PEG myristate, PEG palmitate, and PEG oleate andcombinations thereof.

[0048] The present invention includes an oral self-emulsifyingpharmaceutical formulation with improved bioavailability comprising atherapeutically effective amount of the fenofibrate, a fenofibratederivative or mixtures thereof and dissolved in one or more N-alkylderivative of 2-pyrrolidone or ethylene glycol monoether or mixturesthereof, combined with at least one C₈₋₁₂ fatty acid ester ofpolyethylene glycol or mixtures of C₈₋₁₂ fatty acid ester ofpolyethylene glycol and fatty acids, and at least one non-ionichydrophobic surfactants. The formulation includes the use of surfactantswith an HLB value lower than or equal to about 10. The present inventionalso includes the use of non-ionic surfactants with an HLB value loweror equal to about 6. The present invention also includes the use ofsurfactants selected from mono-acyl glycerides, sorbitan fatty acidesters, sucrose distearate, ethylene glycol monoether and combinationsthereof.

[0049] Non-ionic surfactants used in the oral self-emulsifyingpharmaceutical formulation with improved bioavailability object of thepresent invention may include sorbitan tristearate, sorbitansesquioleate, glyceryl monostearate, sorbitan monooleate, sorbitanmonostearate, sorbitan distearate, propylene glycol monostearate,glyceryl monooleate, glyceryl stearate mono, propylene glycolmonolaurate, glyceryl monolaurate, diethylene glycol monoethyl ether andcombinations thereof.

[0050] The present invention includes an oral self-emulsifyingpharmaceutical formulation with improved bioavailability comprising atherapeutically effective amount of the fenofibrate, a fenofibratederivative or mixtures thereof and one or more N-alkyl derivative of2-pyrrolidone, ethylene glycol monoether and mixtures thereof incombination with at least one C₈₋₁₂ fatty acid ester of polyethyleneglycol or mixtures of C₈₋₁₂ fatty acid ester of polyethylene glycol andfatty acids, at least one non-ionic surfactant with an HLB value higherthan about 10 and at least one non-ionic co-surfactants with an HLBvalue lower than or equal to about 6. The invention includesformulations wherein the combinations of the high HLB and low HLB valuesurfactants have a final HLB value equal to or lower han 10.

[0051] The present invention includes an oral self-emulsifyingpharmaceutical formulation comprising a fibrate dissolved in a fibratesolubilizer composed of a non-oily component selected from N-alkylderivative of 2-pyrrolidone, ethylene glycol monoether and mixturesthereof and an oily component comprising one or more C₈₋₁₂fafty acidesters of polyethylene glycol; and at least one surfactant with an HLBvalue lower than or equal to about 10.

[0052] The present invention also includes an oral self-emulsifyingpharmaceutical formulation with improved bioavailability comprising atherapeutically effective amount of the fenofibrate, a fenofibratederivative or mixtures thereof and combinations of one or more N-alkylderivative of 2-pyrrolidone with ethylene glycol monoether, at least oneC₈₋₁₂ fatty acid ester of polyethylene glycol or mixtures of C₈₋₁₂ fattyacid ester of polyethylene glycol and fatty acids, at least onenon-ionic surfactant with an HLB value higher than about 10 selectedfrom sucrose esters, polysorbates, polyethylene glycosylated glycerides,PEGylated glycerides and combinations thereof; and at least onenon-ionic co-surfactant with an HLB value lower or equal to about 6selected from mono-acyl glycerides, sorbitan fatty acid esters, sucrosedistearate, ethylene glycol monoether and combinations thereof whereinthe combination of the high HLB and low HLB value surfactants have afinal HLB value equal to or lower than 10. The invention includes thoseoral self-emulsifying pharmaceutical formulation with improvedbioavailability described above wherein the improvement in C_(max) is atleast 1.2 times that of a commercial formulation such as Lipanthyl®(trade mark of Groupe Fournier) or TriCor® (trade mark of AbbottLaboratories) and/or the AUC_(0-∞) improvement is at least 1.5 timesthat of a commercial formulation such as Lipanthyl ( (trade mark ofGroupe Fournier) or TriCor® (trade mark of Abbott Laboratories).

[0053] All the formulations object of the present invention may beprepared using both micronized and non-micronized fibrate.

[0054] Other commonly used pharmaceutical excipients which may also beadded to the formulations object of the present invention, these mayinclude antioxidants, preservatives or stabilizing agents, such asbutylated hydroxytoluene, butylated hydroxyanisole sodium bisulfide,sodium sulfite, citric acid, ascorbic acid, or EDTA, coloring agents andflavoring agents (to improve patient acceptance, especially for liquiddosage forms), and ingredients used to stabilize gelatin capsules, suchas glycerine, or gelatin.

[0055] The fibrate formulations disclosed are useful in the treatment ofhypercholesterolaemias and hypertriglyceridaemias. According to afurther aspect of the invention, there is provided a method for treatinga patient with hypercholesterolaemia or hypertriglyceridaemia comprisingthe oral administration of a fibrate formulation containing atherapeutically effective dose of fenofibrate, a fenofibrate derivativeor mixtures thereof dissolved in a water miscible solubilizer selectedfrom N-C₁₋₄ alkyl derivative of 2-pyrrolidone, 2-C₆₋₈ ethylene glycolmonoethers, C₈₋₁₂ fatty acid ester of polyethylene glycol orcombinations thereof. The method of treatment may include the use offibrate formulation described above. As will be appreciated by thoseskilled in the art, the formulations object of the present invention canbe used prophylaxis as well as the treatment of established symptoms.

[0056] In an alternate embodiment of the present invention includes theuse of a therapeutically effective dose of fenofibrate, a fenofibratederivative or mixtures thereof dissolved in a water miscible solubilizerselected from N-C₁₋₄ alkyl derivative of 2-pyrrolidone, C₆₋₈ ethyleneglycol monoethers, C₈₋₁₂ fatty acid ester of polyethylene glycol, fattyacids or combinations thereof in the preparation of a medicament for thetreatment of hypercholesterolaemias and hypertriglyceridaemias.

[0057] The present invention includes a solubilization process offenofibrate, fenofibrate derivative or mixtures thereof whereinfenofibrate, fenofibrate derivative or combinations thereof aresolubilized in N-alkyl derivative of 2-pyrrolidone or mixtures of N-C₁₋₄alkyl derivative of 2-pyrrolidones or combinations of N-C₁₋₄ alkylderivative of 2-pyrrolidone with C₆₋₈ ethylene glycol monoethers. TheNMP is included in the scope of the invention.

[0058] A further aspect of the present invention includes a process forimproving the bioavailability of fenofibrate, a fenofibrate derivativeor mixtures thereof comprising dissolving the active agent in watermiscible solubilizer selected from N-alkyl derivative of 2-pyrrolidone,ethylene glycol monoether, C₈₋₁₂ fatty acid ester of polyethyleneglycol, fatty acids or combinations thereof. The present inventionincludes a process for improving the bioavailability of fenofibrate or afenofibrate derivative comprising dissolving the fenofibrate or afenofibrate derivative in N-methyl-2-pyrrolidone.

[0059] The scope of the invention includes a pharmaceutical dosage unitfor oral administration comprising of a fibrate formulation containing atherapeutically effective dose of fenofibrate or a fenofibratederivative dissolved in N-alkyl derivative of 2-pyrrolidone, ethyleneglycol monoether, C₈₋₁₂ fatty acid ester of polyethylene glycol, fattyacids, or combinations thereof.

[0060] The scope of the invention includes a pharmaceutical dosage unitfor oral administration comprising of a fibrate formulation containing atherapeutically effective amount of the fenofibrate, a fenofibratederivative or mixtures thereof and one or more N-alkyl derivative of2-pyrrolidone, ethylene glycol monoether and mixtures thereof incombination with at least one of C₈₋₁₂ fatty acid ester of polyethyleneglycol, fatty acids an mixtures thereof, and at least one non-ionicsurfactant with an HLB value lower than about 10.

[0061] The scope of the invention includes a pharmaceutical dosage unitfor oral administration comprising of a self emulsifying fibrateformulation containing a therapeutically effective amount of thefenofibrate, a fenofibrate derivative or mixtures thereof and one ormore N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether andmixtures thereof in combination with at least one of C₈₋₁₂fatty acidester of polyethylene glycol or mixtures of C₈₋₁₂ fatty acid ester ofpolyethylene glycol and fatty acids, at least/one non-ionic surfactantwith an HLB value higher than about 10 and at least one non-ionicco-surfactants with an HLB value lower than or equal to about 6. Theinvention includes a pharmaceutical dosage unit for oral administrationcomprising of a self-emulsifying fibrate formulation wherein thecombinations of the high HLB and low HLB value surfactants have a finalHLB value equal to or lower than 10.

[0062] In an alternate embodiment of the present invention a method ofpreparation for a oral formulation of fenofibrate or fenofibratederivative with an improved bioavailability comprising:

[0063] dissolving the fenofibrate, fenofibrate derivative or mixturesthereof in an appropriate volume of water miscible solubilizer selectedfrom N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether,C₈₋₁₂ fatty acid ester of polyethylene glycol or combinations thereof toobtain a fenofibrate solution; and

[0064] incorporating the fibrate solution into a capsule.

[0065] The present process may additionally include the banding of thecapsule to prevent leakage.

[0066] In an alternate embodiment of the present invention a method ofpreparation for a oral formulation of fenofibrate or fenofibratederivative with an improved bioavailability comprising:

[0067] dissolving the fenofibrate, fenofibrate derivative or mixturesthereof in an appropriate volume of water miscible solubilizer selectedfrom N-alkyl derivative of 2-pyrrolidone, C₆₋₈ ethylene glycolmonoethers, C₈₋₁₂ fatty acid ester of polyethylene glycol, mixtures ofC₈₋₁₂ fatty acid ester of polyethylene glycol and fatty acids, orcombinations thereof; and

[0068] incorporating the fenofibrate formulation into a capsule.

[0069] In an alternate embodiment of the present invention a method ofpreparation for a oral formulation of fenofibrate or fenofibratederivative with an improved bioavailability comprising:

[0070] dissolving the fenofibrate, fenofibrate derivative or mixturesthereof in an appropriate volume of water miscible solubilizer selectedfrom combinations of one or more N-alkyl derivative of 2-pyrrolidone,with ethylene glycol monoether or C₈₋₁₂ fatty acid ester of polyethyleneglycol or fatty acids or mixtures thereof; and asurfactant/co-surfactant mixture comprising at least one non-ionicsurfactants with an HLB value higher or equal to about 10 and least onenon-ionic co-surfactants with an HLB value lower or equal to about 6;and

[0071] incorporating the fenofibrate formulation into a capsule.

[0072] In an alternate embodiment of the present invention a method ofpreparation for a oral formulation of fenofibrate or fenofibratederivative with an improved bioavailability comprising:

[0073] dissolving the fenofibrate, fenofibrate derivative or mixturesthereof in an appropriate volume of a fibrate solubilizers defined aboveto obtain a fenofibrate solution;

[0074] mixing the fenofibrate solution with an appropriate amount of amolten gelling agent to obtain a hot fenofibrate gel; and

[0075] incorporating the fenofibrate gel into a capsule.

[0076] In an alternate embodiment of the present invention a method ofpreparation for a oral formulation of fenofibrate or fenofibratederivative with an improved bioavailability comprising:

[0077] dissolving the fenofibrate, fenofibrate derivative or mixturesthereof in an appropriate volume of a fibrate solubilizers defined aboveto obtain a fenofibrate solution;

[0078] the liquid solution is mixed with appropriate amounts of anadsorbing powder (suitable adsorbing powder include dibasic calciumphosphate); to obtain a free flowing powder mixture; and

[0079] incorporation of said free flowing powder mixture into a capsule.

[0080] The present invention also includes a commercial packagecontaining a fenofibrate formulation containing a therapeuticallyeffective dose of fenofibrate, a fenofibrate derivative or mixturesthereof dissolved water miscible solubilizer selected from N-C₁₋₄ alkylderivative of 2-pyrrolidone, C₆₋₈ ethylene glycol monoethers, C₈₋₁₂fatty acid ester of polyethylene glycol, fatty acids or combinationsthereof. The formulation may further contain one or more non-ionicsurfactants. The commercial package further includes instructions forthe use of the pharmaceutical formulation in the treatment ofhypercholesterolaemias and hypertriglyceridaemias in mammals. Ifrequired, the pharmaceutical formulation is admixed with apharmaceutically acceptable carrier, excipient or adjuvant. Thepharmaceutical agent may be incorporated into a drug delivery devicesuitable for oral administration and enclosed in a pharmaceuticalacceptable container.

[0081] The following examples illustrate the present invention in amanner of which it can be practiced but, as such, should not beconstrued as limitations upon the overall scope of the processes of thisinvention.

EXAMPLE 1 Liquid Formulation

[0082] Formulation PD0106-40B was prepared by first dissolving theactive (fenofibrate) in appropriate amounts of NMP. Upon completedissolution of the drug in NMP, the remaining excipients were added andthe final solution was encapsulated in size 0 hard gelatin capsules. Thefilled capsules were then banded using a Quali-Seal lab top bandingmachine to prevent leakage of the fill contents from the capsules.

[0083] Formulation PD01 06-50 was prepared similarly in that the drugwas first dissolved in NMP and then an appropriate amount of a moltenagent such as polyglycolyzed glyceride (e.g. Gelucire 50/13) was addedto this solution. The hot melt was encapsulated into size 1 hard gelatincapsules. The solution in the capsules congealed upon reaching roomtemperature and thus the final state of the fill material wassemi-solid, gel-like, matter. This formulation is advantageous in thatonce processing step, namely leak proof banding, is eliminated from themanufacturing scheme. TABLE 2 Composition of Typical Formulations ofFenofibrate PD0106-40B PD0106-50 Ingredients A B A B Fenofibrate 67 1567 20 NMP 89.4 20 67 20 Captex 200 179 40 — — Gelucire 44/14 89 20Cremophor RH 11 2.5 — — 40 Span 80 11 2.5 — — Gelucire 50/13 — — 201 60

[0084] Content uniformity tests were conducted by determining the amountof fenofibrate in each of 10 capsules (Samples A through J) using a highpressure liquid chromatography (HPLC) methodology specific forfenofibrate detection. The relative standard deviation (RSD) of theaverage of 10 capsules is then taken as an indicator of contentuniformity with %RSD<5.0 as passing. The content uniformity data isgiven in Table 2 below. TABLE 3 Content Uniformity Data for FenofibrateCapsule Formulation PD0106-32B Sample X Y A 66.46 99.2 B 67.85 101.3 C66.73 99.6 D 65.06 97.1 E 69.47 103.7 F 67.27 100.4 G 66.20 98.8 H 66.98100.0 I 67.84 101.3 J 67.20 100.3 Mean 67.11 100.2 % RSD 1.74

EXAMPLE 2 Biologic Activity

[0085] Formulations tested were administered orally to dogs using 67 mgcapsules of enofibrate. Two formulations containing NMP as a solubilizerwere tested in vivo as part of the dog study (n=5). The formulationswere prepared similar to that described in example 1. Lipanthyl®(current marketed fenofibrate product) served as the referenceformulation, and the two test formulations were liquid filled(PD0106-40B) and gel filled (PD0106-50) capsules. TABLE 4 PlasmaConcentrations of Fenofibrate in Fasted Dogs after a 67 mg DoseFormulation (Fenofibrate C_(max) T_(max) AUC₀₋₂₄ % Strength) (μg/ml)(hr) (μg.hr/ml) Enhancement Lipanthyl ® SD 1.88 1.6 11.08 — 67 mg 0.970.9 9.42 PD0106-40B SD 6.11 1.4 29.96 270 67 mg 2.49 0.5 11.87 PD0106-50SD 3.60 0.9 18.11 164 67 mg 1.06 0.2 3.65

[0086] The data summarized in Table 3. The mean C_(max) for Lipanthyl®,PD0106-40B, and PD0106-50 were 1.88, 6.11, and 3.60 μg/ml, respectively.The mean AUC₀₋₂₄ for Lipanthyl®, PD0106-40B, and PD0106-50 were 11.08,29.96, and 18.11 μg.hr/ml, respectively. Both test formulations wereeffective in significantly increasing the C_(max) and AUC₀₋₂₄ comparedto Lipanthyl®.

[0087] Note:

[0088] Lipanthyl is a registered trademark of Groupe Fournier and isused as a reference formulation.

EXAMPLE 3 Semi-solid Fenofibrate Formulation

[0089] Formulations are prepared following the procedure outlined inExample 1. TABLE 5 Examples of formulations of fenofibrate in hardgelatin capsule: Ingredient Amount Fenofibrate 150 mg 54 mg 54 mg (20%W/W) (20% W/W) (20% W/W) NMP 150 mg 54 mg 40.5 mg (20% W/W) (20% W/W)(15% W/W) Gelucire 50/13 450 mg 162 mg 175.5 mg (60% W/W) (60% W/W) (65%W/W) TOTAL 750 mg 270 mg 270 mg

EXAMPLE 4 Self-Emulsifying Formulations

[0090] A) Formulation PD0106-36 and PD0106-72

[0091] The formulations were prepared by first dispersing non-micronizedfenofibrate in appropriate amounts of DGME. Upon complete wetting anddispersion of the drug in DGME, the remaining excipients were added andthe final formulation was in the form of a solution. This solution wasencapsulated in size 0 hard gelatin capsules. The filled capsules werethen banded using a Quali-Seal lab top banding machine to preventleakage of the fill contents from the capsules. TABLE 6A Composition ofA Self-Emulsifying Formulation of Fenofibrate PD0106-72 PD0106-36Ingredients A B A* B Fenofibrate 54 15 67 15 Transcutol ® P 108 30 13430 (DGME) Captex ® 162 45 201 45 200 Labrasol ® 18 5 22 5 Span ® 80 18 522 5

[0092] Note:

[0093] Transcutol® P is a trade name for Diethylene Glycol MonoethylEther, USP/NF, and is marketed by Gattefosse Corp.

[0094] Captex® 200 is a trade name for Propylene GlycolDicaprylate/Dicaprate and marketed by Abitec Corp.

[0095] Labrasol® is a trade name for Caprylocaproyl Macrogolglycerides,EP, and is marketed by Gattefosse Corp.

[0096] Span® 80 is a trade name for sorbitan monooleate and marketed byICI Chemical.

[0097] Content uniformity tests were conducted by determining the amountof fenofibrate in each of 10 capsules (Samples A through J) using a highpressure liquid chromatography (HPLC) methodology specific forfenofibrate detection. The relative standard deviation (RSD) of theaverage of 10 capsules is then taken as an indicator of contentuniformity with %RSD<5.0 as passing. The content uniformity data isgiven in Table 6C below.

[0098] B) Formulation PD0106-40B

[0099] Formulation PD0106-40B was prepared by first dissolving thenon-micronized fenofibrate in appropriate amounts of NMP. Upon completedissolution of the drug in NMP, the remaining excipients were added andthe final solution was encapsulated in size 0 hard gelatin capsules. Thefilled capsules were then banded using a Quali-Seal lab top bandingmachine to prevent leakage of the fill contents from the capsules. TABLE6B Composition of A Self-Emulsifying PD0106-40B Formulation ofNon-Micronized Fenofibrate PD0106-40B Ingredients A B Fenofibrate 67 15NMP 89.4 20 Captex ® 200 179 40 Gelucire ® 44/14 89 20 Cremophor ® 112.5 RH 40 Span ® 80 11 2.5

[0100] TABLE 6C Content Uniformity Data for Fenofibrate CapsuleFormulation PD0106-36 Sample mg % A 63.00 94.0 B 71.75 107.1 C 71.75107.1 D 65.30 97.5 E 65.91 98.4 F 70.59 105.4 G 72.57 108.3 H 68.25101.90 I 65.03 97.1 J 67.46 100.7 Mean 68.16 101.8 % RSD 4.92

[0101] TABLE 6D Self-emulsifying system with NMP/Captex 200 as thesolubilizer PD0106-77A* Ingredients A B(mg) Fenofibrate 15% 300 NMP 30%600 Captex 200 45% 900 Labrasol 5% 100 Span 80 5% 100

[0102] TABLE 6E Self-emulsifying system with NMP/Transcutol/Captex 200mixture as the solubilizer PD0106-77C* Ingredients A B (mg) Fenofibrate15% 300 Transcutol 24% 480 NMP 6% 120 Captex 200 45% 900 Labrasol 5% 100Span 80 5% 100

[0103] TABLE 6F Self-emulsifying system with NMP/Transcutol/Captex 200mixture as the solubilizer PD0106-77D* Ingredients A B (mg) Fenofibrate15% 300 Transcutol 15% 300 NMP 15% 300 Captex 200 45% 900 Labrasol 5%100 Span 80 5% 100

[0104] TABLE 6G Self-emulsifying system with NMP/Transcutol/Miglyol 812mixture as the solubilizer PD0106-77F* Ingredients A B (mg) Fenofibrate15% 300 Transcutol 24% 480 NMP 6% 120 Miglyol 812 45% 900 Labrasol 5%100 Span 80 5% 100

[0105] Note:

[0106] Miglyol is a registered trade mark for of Caprylic-/Capric acidTriglycerides composed of saturated C₈ (50-65%) and C₁₀ (30-45%)triglycerides and owned by Dynamit Nobel Aktiengesellschaft CorporationTABLE 6H Self-emulsifying system with NMP/Transcutol/fatty acids/Captex200 mixture as the solubilizer PD0106-77G* Ingredients A B (mg)Fenofibrate 15% 300 Transcutol 14% 280 NMP 14% 280 Captex 200 45% 900Labrasol 5% 100 Capric acid 1% 20 Caprylic acid 1% 20 Span 80 5% 100

[0107] TABLE 6I Self-emulsifying system with NMP/Transcutol/fattyacid/Miglyol 812 mixture as the solubilizer PD0106-77H* Ingredients A B(mg) Fenofibrate 15% 300 Transcutol 14% 280 NMP 14% 280 Miglyol 812 45%900 Labrasol 5% 100 Capric acid 1% 20 Caprylic acid 1% 20 Span 80 5% 100

EXAMPLE 5 In Vivo Activity of Self-Emulsifying Formulation

[0108] Formulations tested were administered orally to dogs using 67 mgcapsules of fenofibrate. The self-emulsifying formulation of Example 1(Table 1A) was tested in vivo as part of the dog study (n=5). Lipanthyl®67 mg (current marketed fenofibrate product) served as the referenceformulation, and the test formulation was liquid filled hard gelatincapsule.

[0109] The data summarized in Table 7. TABLE 7 Plasma Concentrations ofFenofibrate in Fasted Dogs after a 67 mg Dose C_(max) T_(max) AUC₀₋₂₄Formulation (μg/ml) (hr) (μg.hr/ml) % Enhancement* Lipanthyl ® 1.88 1.611.08 — SD 0.97 0.9 9.42 PD0106-36 4.17 1.1 24.17 218 SD 1.83 0.5 7.96

[0110] The mean C_(max) for Lipanthyl® and PD0106-36 were 1.88 and 4.17μg/ml, respectively. The mean AUC₀₋₂₄ for Lipanthyl® and PD0106-36 were11.08 and 24.17 μg.hr/ml, respectively. The test formulation waseffective in significantly increasing the C_(max) and AUC₀₋₂₄ comparedto Lipanthyl®.

[0111] Note:

[0112] Lipanthyl® is a marketed product of Groupe Fournier and is usedas a reference formulation.

EXAMPLE 6 Self-Emulsifying Properties

[0113] To evaluate the behavior of the self-emulsifying formulation asit becomes exposed to aqueous media, five grams of various fenofibratesolution formulations were prepared and known amounts of water wereadded to the respective formulas. The compositions of the formulationsalong with the outcome of the water addition are shown in Table 8. TABLE8 Effect of water addition on various liquid fenofibrate formulationsCOMPOSITION FORMULATION* (% W/W) OBSERVATION PD0106-61A Fenofibrate, 20%Upon addition of only 1 ml of water, Transcutol P, 80% fenofibratecrashed out of solution and large crystal precipitates appeared.PD1016-61B Fenofibrate, 15% Upon addition of water the self- TranscutolP, 30% emulsifying formulation turned into a Captex 200, 45% whiteemulsion with no precipitates Labrasol, 5% forming even after additionof 11 ml of Span 80, 5% water, which was more than twice the volume ofthe starting formulation. PD0106-61C Fenofibrate, 6.25% Upon addition ofonly 2 ml of water, Transcutol P, 93.75% fenofibrate crashed out ofsolution and large crystal precipitates appeared. PD0106-65AFenofibrate, 15% Upon addition of only 1 ml of water, Transcutol P, 75%fenofibrate crashed out of solution and Labrasol, 5% large crystalprecipitates appeared. Span 80, 5% PD0106-65B Fenofibrate, 15% Uponaddition of only 2 ml of water, Captex 200, 75% fenofibrate crashed outof solution and Labrasol, 5% crystalline precipitates appeared. Span 80,5% PD0106-65C Fenofibrate, 15% Upon addition of water the self- Captex200, 45% emulsifying formulation turned into a N-methyl-2-pyrrolidonewhite emulsion with no precipitates (NMP), 30% forming even afteraddition of 5 ml of Labrasol, 5% water. Span 80, 5% PD0106-65DFenofibrate, 15% Upon addition of only 2 ml of water, NMP, 75%fenofibrate crashed out of solution and Labrasol, 5% crystallineprecipitates appeared. Span 80, 5% PD0106-65E Fenofibrate, 15% Uponaddition of only 2 ml of water, Transcutol P, 45% fenofibrate crashedout of solution and NMP, 30% crystalline precipitates appeared.Labrasol, 5% Span 80, 5% PD0106-66 Fenofibrate, 15% Upon addition ofonly 1 ml of water, Transcutol, 80% fenofibrate crashed out of solutionand Labrasol, 5% large crystal precipitates appeared.

[0114] The self-emulsifying formulations (PD0106-61B and PD0106-65C) didnot crash in presence of excessive amounts of water, whereas all otherformulations containing various solutions of fenofibrate severelycrashed out of solution by forming large crystalline particulates uponaddition of 1 or 2 ml of water. Our self-emulsifying formulations aresuperior to solution formulations containing the drug and a solubilizer.

1—A pharmaceutical formulation of a fibrate with improved oral bioavailability comprising a fibrate selected from fenofibrate , derivative of fenofibrate or mixtures thereof dissolved in a water miscible fibrate solubilizer selected from N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C₈₋₁₂ fatty acid ester of polyethylene glycol, fatty acids and combinations thereof; wherein the fibrate to solubilizer weight ratio is between about 1:1 and about 1:100. 2—A formulation according to claim 1 wherein the formulation further includes at least one surfactant. 3—A formulation according to claim 1 wherein the formulation further includes a gelling agent. 4—A formulation according to claim 2 wherein the formulation is a self-emulsifying formulation wherein the water miscible fibrate solubilizer is selected from N-C₁₋₄ alkyl derivative of 2-pyrrolidone or C₆₋₈ ethylene glycol monoether and mixtures thereof, in combination with at least one C₈₋₁₂ fatty acid ester of polyethylene glycol and at least one non-ionic surfactant with a HLB value lower than or equal to
 10. 5—A formulation according to claim 2 wherein the solubilizer comprises a non-oily component selected from N-C₁₋₄ alkyl derivative of 2-pyrrolidone, C₆₋₈ ethylene glycol monoether and combinations thereof; and an oily component selected from C₈₋₁₂ fatty acid ester of polyethylene glycol, fatty acids and mixtures thereof. 6—A formulation according to claim 2 wherein the surfactant is nonionic hydrophobic surfactant. 7—A formulation according to claims 1 or 5 wherein the solubilizer is selected from mixtures of N-C₁₋₄ alkyl derivative of 2-pyrrolidones, C₆₋₈ ethylene glycol monoethers or combinations thereof; with one or more polyethylene glycol mono- and diester of C₈₋₁₂ fatty acids or combinations of polyethylene glycol mono- and diester of C₈₋₁₂ fatty acids and fatty acids. 8—A formulation according to claim 7 wherein the weight ratio of the N-C₁₋₄ alkyl derivative of 2-pyrrolidone or a C₆₋₈ ethylene glycol monoethers or combinations thereof to one or more polyethylene glycol mono- and diester of C₈₋₁₂ fatty acids or combinations of polyethylene glycol mono- and diester of C₈₋₁₂ fatty acids and fatty acids is between about 100:1 to about 1:4. 9—A formulation according to claim 1 wherein the N-C₁₋₄ alkyl derivative of 2-pyrrolidone is selected from N-Methyl-2-Pyrrolidone, N-Ethyl-2-pyrrolidone, N-Propyl-2-pyrrolidone, N-Isopropyl-2-pyrrolidone, N-Butyl-2-pyrrolidone, and N-(2-Hydroxyethyl)-2-pyrrolidone or mixtures thereof. 10—A formulation according to claim 9 wherein the N-C₁₋₄ alkyl derivative of 2-pyrrolidone is N-methyl-2-pyrrolidone. 11—A formulation according to claim 1 wherein the ethylene glycol monoether is diethylene glycol monoethyl ether. 12—A formulation according to claim 6 wherein the surfactant has a HBL value lower than or equal to
 10. 13—A formulation according to claim 2 wherein the formulation further includes at least one co-surfactant. 14—A formulation according to claim 13 wherein the surfactant/co-surfactant combination has a HLB value lower than or equal to
 10. 15—A formulation according to claim 14 wherein the formulation further includes a surfactant selected from non-ionic surfactants with HLB values greater than 10 and at least one non-ionic co-surfactant with low HLB values lower than or equal to
 6. 16—A formulation according to claim 15 wherein the co-surfactant is at least one non-ionic surfactants with HLB value between 10 and 18, one or more non-ionic co-surfactant with a HLB value between 2 and 6, provided that the HBL value of the combination is less than or equal to
 10. 17—A self-emulsifying oral pharmaceutical formulation with improved bioavailability comprising: a therapeutically effective amount of the fenofibrate or a fenofibrate derivative; at least one non-ionic hydrophobic surfactant; and a water miscible fibrate solubilizer selected from N-C₁₋₄ alkyl derivative of 2-pyrrolidone, C₃₋₈ ethylene glycol monoether, or combinations thereof; mixed with at least one of C₈₋₁₂ fatty acid ester of polyethylene glycol, fatty acids or mixtures thereof. 18—A method of treating endogenous hyperlipidaemias, hypercholesterolaemias and hypertriglyceridaemias in mammals comprising the administration of a fibrate formulation of any of claims 1 or
 5. 19—A process for improving the bioavailability of fenofibrate or a fenofibrate derivative comprising dissolving the fenofibrate or a fenofibrate derivative in N-methyl-2-pyrrolidone. 20—A pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C₈₋₁₂ fatty acid ester of polyethylene glycol, fatty acids, or combinations thereof. 21—A pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof and one or more N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether and mixtures thereof in combination with at least one of C₈₋₁₂ fatty acid ester of polyethylene glycol, fatty acids and mixtures thereof, and at least one non-ionic hydrophobic surfactant or surfactant combinations. 